Emend capsules 125 mg (1) + capsules 80 mg (2) combi-pack No. 3

Instructions for use Emend capsules 125 mg (1) + capsules 80 mg (2) combination pack No. 3

Composition

active ingredient: aprepitant;

1 capsule contains 80 mg or 125 mg of aprepitant;

excipients: sucrose, microcrystalline cellulose, hydroxypropylcellulose, sodium lauryl sulfate.

Capsule shell – gelatin, titanium dioxide (E 171).

The 125 mg capsule shell also contains red iron oxide (E 172) and yellow iron oxide (E 172).

Dosage form

Capsules.

Main physicochemical properties:

80 mg capsules: white opaque hard gelatin capsule with “461” and “80 mg” printed radially in black ink;

125 mg capsules: opaque hard gelatin capsule with white body and pink cap with “462” and “125 mg” printed radially in black ink.

Pharmacotherapeutic group

Drugs affecting the digestive system and metabolism. Antiemetics and drugs that eliminate nausea. Other antiemetics.

ATX code A04A D12.

Pharmacological properties

Pharmacodynamics.

Aprepitant is a selective neurokinin 1 (NK1) receptor antagonist with high affinity for human substance P (a P-neuropeptide of the tachykinin family). Additional screening studies showed that aprepitant was at least 3000-fold more selective for NK1 receptors than for other enzyme, ion channel transporter, and receptor localizations, including dopamine and serotonin receptors, which are targets for chemotherapy-induced nausea and vomiting.

NK1 receptor antagonists, through their central nervous system effects, inhibit the vomiting reflex induced by cytotoxic chemotherapeutic agents such as cisplatin. In preclinical and human positron emission tomography (PET) studies, aprepitant has been shown to penetrate the brain and bind to brain NK1 receptors. Aprepitant has a long-lasting central nervous system effect, suppressing both the acute and delayed phases of the cisplatin-induced vomiting reflex, and augmenting the antiemetic activity of the 5HT3 receptor antagonist ondansetron and the corticosteroid dexamethasone against cisplatin-induced vomiting.

Pharmacokinetics.

Absorption. The mean absolute oral bioavailability of aprepitant is 67% for the 80 mg capsule and 59% for the 125 mg capsule. The mean maximum plasma concentration (Cmax) of aprepitant is reached after approximately 4 hours (tmax). Oral administration of the capsule with a standard breakfast of approximately 800 kcal results in a 40% increase in the AUC of aprepitant. This increase is considered to be of no clinical significance.

The pharmacokinetics of aprepitant are non-linear over the clinical dose range. In healthy young adults, the increase in AUC0-∞ was 26% greater than dose-proportional after single doses of 80 mg and 125 mg in the fed state.

Following a single oral dose of Emend® 125 mg on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0-24h (mean ± SD) was 19.6 ± 2.5 μg × h/mL and 21.2 ± 6.3 μg × h/mL on Days 1 and 3, respectively. Cmax was 1.6 ± 0.36 μg/mL and 1.4 ± 0.22 μg/mL on Days 1 and 3, respectively.

Distribution: Aprepitant is extensively bound to plasma proteins, averaging 97%. The geometric mean apparent volume of distribution at steady state (Vdss) in humans is approximately 66 L.

Metabolism. Aprepitant undergoes extensive metabolism. In healthy young volunteers, aprepitant accounted for approximately 19% of the radioactivity in plasma within 72 hours after a single intravenous administration of 100 mg of [14C]-fosaprepitant (the precursor of aprepitant), indicating the presence of metabolites in plasma. Twelve metabolites of aprepitant have been identified in human plasma. Aprepitant is metabolized primarily by oxidation at the morpholine ring and its side chains, and the resulting metabolites were only weakly active. In vitro studies using human liver microsomes have shown that aprepitant is metabolized primarily by CYP3A4, with minor potential contributions from CYP1A2 and CYP2C19.

Elimination: Aprepitant is not excreted unchanged in the urine. Metabolites are excreted in the urine and bile in the feces. Following a single intravenous dose of 100 mg [14C]-fosaprepitant (the precursor of aprepitant) to healthy volunteers, 57% of the radioactivity was recovered in the urine and 45% in the feces.

The plasma clearance of aprepitant is dose-dependent, decreasing with increasing dose, and ranges from approximately 60 to 72 mL/min over the therapeutic dose range. The terminal half-life ranges from approximately 9 to 13 hours.

Pharmacokinetics in individual groups

Gender. Following a single 125 mg oral dose of Emend®, the Cmax of aprepitant is 16% higher in women than in men. The elimination half-life of aprepitant is 25% shorter in women than in men, and Tmax is reached at approximately the same time. These differences are not considered clinically significant. No dose adjustment of Emend® is necessary based on the patient's gender.

Hepatic impairment. Mild hepatic impairment (Child-Pugh Class A) has no clinically significant effect on the pharmacokinetics of aprepitant; no dose adjustment is necessary for these patients. No conclusions can be drawn from the available data regarding the effect of moderate hepatic impairment (Child-Pugh Class B) on the pharmacokinetics of aprepitant. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh Class C).

Renal impairment: Aprepitant at a single dose of 240 mg has been administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) and to patients with end-stage renal disease requiring hemodialysis.

In patients with severe renal impairment, the AUC0-¥ of total aprepitant (unbound and protein-bound) was decreased by 21% and the Cmax was decreased by 32%, compared to healthy volunteers. In patients with end-stage renal disease undergoing hemodialysis, the AUC0-¥ of total aprepitant was decreased by 42% and the Cmax was decreased by 32%. Due to the small decrease in plasma protein binding of aprepitant associated with renal disease, the AUC of pharmacologically active unbound aprepitant was not significantly changed in patients with renal impairment compared to healthy volunteers. Hemodialysis performed 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.

There is no need to change the dosage regimen of Emend® for patients with impaired renal function and patients with end-stage renal disease undergoing hemodialysis.

Relationship between concentration and effect

Positron emission tomography studies using a highly specific NK1 receptor label in healthy young men demonstrated that aprepitant penetrates the brain and fills NK1 receptors in a dose-dependent and plasma-concentration-dependent manner. Plasma concentrations of aprepitant achieved with a three-day regimen of aprepitant provide 95% occupancy of brain NK1 receptors.

Indication

As part of combination therapy:

prevention of acute and delayed nausea and vomiting associated with cisplatin-based anticancer chemotherapy with high emetogenic risk in adults;

prevention of nausea and vomiting associated with the use of anticancer chemotherapy with moderate emetogenic risk in adults.

Contraindication

Emend® is contraindicated in patients with hypersensitivity to any component of the drug.

Emend® should not be used concomitantly with pimozide, terfenadine, astemizole, and cisapride.

Interaction with other medicinal products and other types of interactions

Aprepitant (125 mg/80 mg) is a substrate, moderate inhibitor, and inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. CYP3A4 activity is inhibited during treatment with Emend®. After discontinuation of treatment, Emend® causes a mild, transient induction of CYP2C9, CYP3A4, and glucuronidation. Aprepitant does not appear to interact with the P-glycoprotein transporter, which supports the lack of interaction of aprepitant with digoxin.

Effect of aprepitant on the pharmacokinetics of other active substances.

Inhibition of CYP3A4 activity

As a moderate inhibitor of CYP3A4, aprepitant (125 mg/80 mg) may increase plasma concentrations of active substances metabolized by CYP3A4 when co-administered. Total exposure to orally administered CYP3A4 substrates may increase approximately 3-fold during a 3-day treatment with Emend®; it is expected that the effect of aprepitant on plasma concentrations of intravenously administered CYP3A4 substrates will be less pronounced. Emend® should not be administered concomitantly with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 activity by aprepitant may result in increased plasma concentrations of these active substances, potentially leading to serious or life-threatening reactions. It is recommended to take Emend® with caution when taking it with orally administered active substances that are metabolized to a greater extent by CYP3A4 and have a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl and quinidine.

Dexamethasone. When co-administered with Emend® 125 mg/80 mg, the usual oral dose of dexamethasone should be reduced by approximately 50%. The dose of dexamethasone in clinical trials for the prevention of chemotherapy-induced nausea and vomiting (CINV) was selected taking into account the interaction of the active substances. Emend® 125 mg co-administered with oral dexamethasone 20 mg on day 1 and Emend® 80 mg co-administered with oral dexamethasone 8 mg on days 2 to 5 increased the area under the concentration-time curve (AUC) of dexamethasone (a CYP3A4 substrate) by 2.2-fold on days 1 and 5.

Methylprednisolone. When co-administered with Emend® 125 mg/80 mg, the usual intravenous dose of methylprednisolone should be reduced by approximately 25% and the usual oral dose of methylprednisolone should be reduced by approximately 50%. Emend®, when administered at a dose of 125 mg on day 1 and 80 mg/day on days 2 and 3, increased the AUC of methylprednisolone (a CYP3A4 substrate) 1.3-fold on day 1 and 2.5-fold on day 3 when methylprednisolone was co-administered at a dose of 125 mg intravenously on day 1 and 40 mg orally on days 2 and 3.

During long-term treatment with methylprednisolone, the AUC of methylprednisolone may decrease at the latest 2 weeks after starting Emend® due to the activating effect of aprepitant on CYP3A4. This effect is expected to be more pronounced with oral methylprednisolone.

Chemotherapeutic drugs

In pharmacokinetic studies, Emend®, when administered at a dose of 125 mg on day 1 and 80 mg/day on days 2 and 3, did not affect the pharmacokinetics of docetaxel administered intravenously on day 1 or vinorelbine administered intravenously on days 1 or 8. Since the effect of Emend® on the pharmacokinetics of oral CYP3A4 substrates is more pronounced than the effect on the pharmacokinetics of intravenous CYP3A4 substrates, interactions with orally administered chemotherapeutic agents that are primarily or partially metabolized by CYP3A4 (e.g. etoposide, vinorelbine) cannot be excluded. Caution and additional monitoring are recommended in patients receiving drugs that are primarily or partially metabolized by CYP3A4. In the post-marketing period, cases of neurotoxicity (a potential adverse reaction of ifosfamide) have been reported with the concomitant use of aprepitant and ifosfamide.

Immunosuppressants

During a three-day course of NBX therapy, a transient moderate increase followed by a small decrease in exposure of immunosuppressants metabolized by CYP3A4 (e.g., cyclosporine, tacrolimus, everolimus, and sirolimus) is expected. Given the short three-day course of treatment and limited time-dependent changes in exposure, dose reduction of immunosuppressants is not recommended during the three-day co-administration with Emend®.

Midazolam

The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized by CYP3A4 (alprazolam, triazolam) should be considered when these drugs are co-administered with Emend® (125 mg/80 mg).

Emend® increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on day 1 and 3.3-fold on day 5 when co-administered with a single oral dose of midazolam 2 mg on days 1 and 5 during a course of treatment with Emend® at a dose of 125 mg on day 1 and at a dose of 80 mg/day on days 2 to 5.

In another study with intravenous midazolam, Emend® was administered at a dose of 125 mg on day 1 and 80 mg/day on days 2 and 3, and midazolam was administered intravenously at a dose of 2 mg prior to the 3-day course of Emend® and on days 4, 8, and 15. Emend® increased midazolam AUC by 25% on day 4 and decreased midazolam AUC by 19% on day 8 and 4% on day 15. These effects were considered to be of no clinical significance.

In a third study with intravenous and oral midazolam, Emend® was administered at a dose of 125 mg on day 1 and 80 mg/day on days 2 and 3 together with ondansetron 32 mg on day 1, dexamethasone 12 mg on day 1 and 8 mg on days 2–4. This combination (i.e. Emend®, ondansetron and dexamethasone) reduced midazolam AUC by 16% on day 6, 9% on day 8, 7% on day 15 and 17% on day 22. These effects were not considered to be clinically relevant.

An additional study was conducted with intravenous midazolam and Emend®. Midazolam was administered intravenously at a dose of 2 mg 1 hour after a single oral dose of Emend® 125 mg. The plasma AUC of midazolam increased 1.5-fold. This effect was considered to be of no clinical significance.

As a weak inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant may decrease plasma concentrations of substrates eliminated by these pathways for up to 2 weeks after initiation of treatment. This effect may only be apparent after discontinuation of Emend®. For CYP2C9 and CYP3A4 substrates, the induction is transient, with a peak effect occurring 3–5 days after the end of a 3-day Emend® treatment. This effect persists for several days, then slowly declines and is not clinically significant by 2 weeks after discontinuation of Emend® treatment. A weak induction of glucuronidation has also been observed with oral administration of 80 mg aprepitant for 7 days. There is no information on the effects on CYP2C8 and CYP2C19. Caution is advised when warfarin, acenocoumarol, tolbutamide, phenytoin or other active substances metabolised by CYP2C9 are administered during this period.

Warfarin: In patients receiving chronic warfarin therapy, prothrombin time (PT) should be closely monitored during treatment with Emend® and for 2 weeks after each 3-day course of Emend® for the prevention of chemotherapy-induced nausea and vomiting. When a single dose of 125 mg Emend® on Day 1 and 80 mg/day on Days 2 and 3 was administered to healthy volunteers stabilized on continuous warfarin, Emend® had no effect on plasma AUC of R(+) or S(-) warfarin measured on Day 3; however, there was a 34% decrease in trough concentration of S(-) warfarin (a CYP2C9 substrate) associated with a 14% decrease in INR 5 days after stopping Emend®.

Tolbutamide: Emend®, administered at a dose of 125 mg on day 1 and 80 mg/day on days 2 and 3, reduced the AUC of tolbutamide (a CYP2C9 substrate) by 23% on day 4, 28% on day 8, and 15% on day 15 when a single oral dose of tolbutamide 500 mg was administered prior to a 3-day course of Emend® and on days 4, 8, and 15.

Hormonal contraceptives

During and for 28 days after use of Emend®, the effectiveness of hormonal contraceptives may be reduced. Alternative or additional methods of contraception should be used during treatment with Emend® and for 2 months after the last dose of Emend®. In a clinical study, single doses of oral contraceptives containing ethinylestradiol and norethindrone were administered from days 1 to 21 with Emend® taken at a dose of 125 mg on day 8 and 80 mg/day on days 9 and 10 with intravenous ondansetron at a dose of 32 mg on day 8 and oral dexamethasone at a dose of 12 mg on day 8 and 8 mg/day on days 9, 10, and 11. From days 9 to 21 of this study, the decrease in ethinylestradiol trough concentrations reached 64% and the decrease in norethindrone trough concentrations reached 60%.

5-HT3 Antagonists: In clinical interaction studies, aprepitant had no clinically significant effect on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Effect of other drugs on the pharmacokinetics of aprepitant.

Emend should be used with caution when co-administered with active substances that inhibit CYP3A4 activity (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and protease inhibitors) as this combination is expected to result in increased plasma concentrations of aprepitant.

Concomitant use of Emend® with active substances that strongly induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as this combination leads to decreased plasma concentrations of aprepitant, which may lead to reduced efficacy of Emend®. Concomitant use of Emend® with herbal preparations containing St. John's wort (Hypericum perforatum) is not recommended.

Ketoconazole.

When a single dose of aprepitant 125 mg was administered on day 5 of a 10-day course of treatment with ketoconazole (a potent CYP3A4 inhibitor) at a dose of 400 mg/day, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold.

Rifampicin.

When a single dose of 375 mg aprepitant was administered on day 9 of a 14-day course of rifampicin (a potent CYP3A4 inducer) at a dose of 600 mg/day, the AUC of aprepitant was decreased by 91% and the mean terminal half-life was decreased by 68%.

Diltiazem.

In patients with moderate hypertension, coadministration of aprepitant 230 mg once daily with diltiazem 120 mg three times daily for 5 days increased the AUC of aprepitant by two-fold and simultaneously increased the AUC of diltiazem by 1.7-fold. This pharmacokinetic interaction had no effect on ECG, heart rate, or blood pressure, independent of changes caused by diltiazem alone.

Paroxetine.

Coadministration of aprepitant 85 mg or 170 mg with paroxetine 20 mg once daily decreased the AUC of both aprepitant and paroxetine by approximately 25% and Cmax by approximately 20%.

Application features

Interactions mediated by CYP3A4.

Emend® should be used with caution in patients taking concomitant medicinal products that are predominantly metabolised by CYP3A4 and have a narrow therapeutic index, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl and quinidine (see section 4.5). In addition, special caution should be exercised when co-administered with irinotecan, as this combination may lead to increased toxicity.

Concomitant use of Emend® with ergot alkaloid derivatives that are CYP3A4 substrates may result in increased plasma concentrations of these active substances. Therefore, caution is recommended due to the potential risk of toxicity associated with ergot.

Concomitant use of Emend® with active substances that strongly induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as this combination leads to decreased plasma concentrations of aprepitant (see section 4.5). Concomitant use of Emend® with herbal preparations containing St. John's wort (Hypericum perforatum) is not recommended.

Emend should be used with caution with active substances that inhibit CYP3A4 activity (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and protease inhibitors), as this combination is expected to lead to increased plasma concentrations of aprepitant (see section 4.5).

Concomitant use with warfarin (CYP2C9 substrate). Concomitant use of Emend® with warfarin results in a decrease in prothrombin time, expressed as the international normalized ratio (INR). In patients receiving continuous warfarin therapy, INR should be closely monitored during treatment with Emend® and for 2 weeks after each 3-day course of Emend® used for the prevention of chemotherapy-induced nausea and vomiting (see section 4.5).

Concomitant use with hormonal contraceptives. During and for 28 days after use of Emend®, the effectiveness of hormonal contraceptives may be reduced. Alternative additional non-hormonal methods of contraception should be used during treatment with Emend® and for 2 months after the last dose of Emend® (see section “Interaction with other medicinal products and other forms of interaction”).

Excipients: Emend® contains sucrose. Therefore, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

Sodium.

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially “sodium-free”.

Use during pregnancy or breastfeeding

Contraception in men and women. The effectiveness of hormonal contraceptives may be reduced during and for 28 days after use of Emend®. Alternative additional non-hormonal methods of contraception should be used during treatment with Emend® and for 2 months after the last dose of Emend®.

Pregnancy: There are no clinical data on the use of aprepitant in pregnant women. The potential for reproductive toxicity of aprepitant has not been fully established since exposure levels in excess of the therapeutic human exposure at the dose administered are not known.

125 mg/80 mg, cannot be achieved in animal studies. These studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. The potential effect of neurokinin regulation on reproductive function is unknown. Emend® should not be used during pregnancy unless clearly necessary.

Breastfeeding. Aprepitant is excreted in the milk of lactating rats. It is not known whether the drug is excreted in human milk, therefore, breast-feeding is not recommended during treatment with Emend®.

Fertility: The potential for aprepitant to affect fertility has not been fully studied, as exposure levels in excess of the human therapeutic exposure cannot be achieved in animal studies. Fertility studies did not indicate direct or indirect adverse effects on mating, fertility, embryonal/fetal development, or sperm count and motility.

The ability to influence the reaction speed when driving or working with other mechanisms

Emend® may have a minor influence on the ability to drive and use machines. Dizziness and fatigue may occur after using the drug.

Method of administration and doses

The capsule should be swallowed whole.

Emend® should be administered for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose of Emend® is 125 mg orally (p/o) 1 hour before chemotherapy (on day 1) and 80 mg once daily in the morning on days 2 and 3.

The following treatment regimens are recommended for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.

Course for chemotherapy with high emetogenic risk

Dexamethasone should be administered 30 minutes before chemotherapy on day 1 and in the morning on days 2 through 4. The dose of dexamethasone was selected with drug interactions in mind.

Course for chemotherapy with moderate emetogenic risk

Dexamethasone should be administered 30 minutes before chemotherapy on day 1. The dose of dexamethasone was selected with drug interactions in mind.

Limited data on the efficacy of combination with other corticosteroids and 5-HT3 antagonists. For further information on concomitant use with corticosteroids, see section 4.5. Interactions with other medicinal products and other forms of interaction. The package leaflet of the concomitantly administered 5-HT3 antagonist should be consulted.

Certain groups of patients.

Elderly patients (≥ 65 years): No dose adjustment is necessary for elderly patients.

Gender: No dose adjustment is necessary based on gender.

Patients with renal impairment: No dose adjustment is necessary for patients with renal impairment or patients with end-stage renal disease undergoing hemodialysis.

Patients with hepatic impairment. No dose adjustment is necessary for patients with mild hepatic impairment. There are limited data in patients with moderate hepatic impairment and no information in patients with severe hepatic impairment. Aprepitant should be used with caution in such patients.

Children

The safety and efficacy of Emend® in children and adolescents (under 18 years of age) have not been established. Data are lacking, and the drug is not recommended for use in these patients.

Overdose

In the event of overdose, Emend® should be discontinued and general supportive care and monitoring should be instituted. Due to the antiemetic activity of aprepitant, agents that induce vomiting will be ineffective. Aprepitant is not removed by hemodialysis.

Side effects

In patients treated with aprepitant during chemotherapy with a high risk of emetogenicity, the following drug-related adverse reactions occurred most frequently: hiccups (4.6%), increased ALT (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2.0%), decreased appetite (2.0%). The most common drug-related adverse reaction reported during treatment with aprepitant during chemotherapy with a moderate risk of emetogenicity in patients was fatigue (1.4%).

The following adverse reactions were observed in a pooled analysis of highly or moderately emetogenic chemotherapy trials at a higher incidence in patients treated with aprepitant than in patients treated with standard therapy, and during postmarketing use.

The frequency is defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (frequency cannot be estimated from the available data).

infrequently

rarely

*Nausea and vomiting were efficacy parameters during the first 5 days of post-chemotherapy treatment and were considered as adverse reactions only after this period.

The nature of adverse reactions that occurred with multiple cycles (up to 6 cycles) of chemotherapy was similar to that observed in 1 cycle.

In an additional active-controlled clinical trial in 1169 patients receiving aprepitant and highly emetogenic chemotherapy, the adverse reaction profile was generally similar to that observed in other highly emetogenic chemotherapy trials with aprepitant.

Non-NBSH research

Additional adverse reactions were observed in patients receiving a single 40 mg dose of aprepitant for the treatment of postoperative nausea and vomiting at a higher frequency than with ondansetron: upper abdominal pain, abnormal bowel sounds, constipation*, dysarthria, dyspnea, hypoaesthesia, insomnia, miosis, nausea, sensory disturbances, gastric discomfort, partial intestinal obstruction*, decreased visual acuity, and wheezing.

*Reported in patients taking high doses of aprepitant.

Expiration date

4 years.

Storage conditions

Store in a place protected from moisture at a temperature not exceeding 30 ºС in the original packaging.

Keep out of reach of children.

Packaging

Combo pack of 3 capsules; 1 capsule of 125 mg + 2 capsules of 80 mg in blisters in a cardboard wrapper; 1 cardboard wrapper in a cardboard box.

Vacation category

According to the recipe.

Producer

Merck Sharp & Doom B.V., Netherlands.

Location of the manufacturer and its address of place of business.

Vaarderweg 39, 2031 BN Haarlem, Netherlands.